We will examine the mechanisms of endothelium-dependent pulmonary arterial relaxation, and test the hypothesis that vasoactive intestinal peptide (VIP), a potent pulmonary vasodilator present in the vicinity of pulmonary arterial endothelial cells, may act as an Endothelium-Derived Relaxing Factor (EDRF). We will also examine the possible mediator role of free radicals as EDRF's. Our specific goals are to: 1) confirm that immunoreactive VIP is closely associated with pulmonary arterial endothelium; 2) establish whether VIP-induced relaxation of PA is independent of the presence of endothelium; 3) examine the binding of the endogenous vasodilators Ach, ATP, Substance P, bradykinin and VIP to endothelial cells from cat pulmonary artery; 4) measure the release of immunoreactive VIP from the pulmonary artery by endothelium-dependent vasodilators; 5) using electron spin resonance and spin trapping techniques, identify the free radical(s) produced by some vasodilators, and its role in the endothelium-dependent relaxation, with or without the release of VIP; and 6) determine the dependence on endothelium of nonadrenergic, noncholinergic relaxation elicited by electrical field stimulation of pulmonary artery, and the role of VIP as a neurotransmitter of this system. The results promise to add valuable new information on the importance of pulmonary arterial endothelium in pulmonary vascular responses, and especially on the identities of endothelium-derived relaxing factors in the pulmonary circulation.